Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: an epigenome-wide association study of 12 metals

Abstract

Background Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6–10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR < 0.05), and for DMRs using comb-p (Sidak p < 0.05). Covariates included biologically relevant variables and estimated cell-type composition. We also performed sex-stratified analyses. Results Pb was associated with decreased methylation of cg20608990 (CASP8) (FDR = 0.04), and Mn was associated with increased methylation of cg02042823 (A2BP1) in cord blood (FDR = 9.73 × 10–6). Both associations remained significant but attenuated in blood DNAm collected at mid-childhood (p < 0.01). Two and nine Mn-associated DMPs were identified in male and female infants, respectively (FDR < 0.05), with two and six persisting in mid-childhood (p < 0.05). All metals except Ba and Pb were associated with ≥ 1 DMR among all infants (Sidak p < 0.05). Overlapping DMRs annotated to genes in the human leukocyte antigen (HLA) region were identified for Cr, Cs, Cu, Hg, Mg, and Mn. Conclusions Prenatal metal exposure is associated with DNAm, including DMRs annotated to genes involved in neurodevelopment. Future research is needed to determine if DNAm partially explains the relationship between prenatal metal exposures and health outcomes.

Prenatal exposure to heavy metal mixtures and anthropometric birth outcomes: a cross-sectional study

“…However, it is predominantly determined by inheritance [ 90 ] and pathways involving many genes and transcription factors [ 91 ]; therefore alternations in head circumference characterize many genetic disorders [ 92 , 93 ] and have been extensively studied. As many of the metals included in this study were previously found to act as genetic modifiers [ 94 – 96 ], suppressing or enhancing fetal expression of genes, it is not unreasonable to assume that interactions between these metals themselves [ 57 ], or with proteins [ 97 ], including transcription factors, could lead to various alterations in newborns’ phenotypes. Recent studies have suggested that metals could also interact with epigenetic processes that may be crucial to intrauterine development [ 98 ], especially in the context of metal mixtures.…”

Associations of Heavy Metals with Activities of Daily Living Disability: An Epigenome-Wide View of DNA Methylation and Mediation Analysis

“…Possibly due to similar population characteristics, cg05825244 (annotated to EBF4 ) was identified to be significantly associated with copper in an EWAS study of 1,243 Chinese individuals, 79 which was consistent with our results. Other EWAS studies associated with manganese, arsenic and cadmium, which were performed in populations such as American mother–infant pairs, 79 Bangladeshi adults, 80 and American Indian tribes, 20 however, did not reported similar genes. We have additionally performed an additional analysis of KEGG and GO pathway, where significant sites enriched mainly involved diverse cellular functions such as neuronal axons, synapses, and ion channel activities that were crucial in brain homeostasis involved in the ADL disability process.…”

Associations of Prenatal First Trimester Essential and Nonessential Metal Mixtures with Body Size and Adiposity in Childhood.

“… 50 Fetal development is a susceptible period of rapid epigenetic reprogramming, and both essential and nonessential metal exposure was shown to influence DNA methylation at birth and in childhood. 51 Programming of metabolic-related genes could influence metabolic trajectories, particularly in periods of accelerated growth. 52 We observed the strongest associations in mid-childhood and adolescence, supporting this hypothesis.…”